Diabetes and Vitamin D

Diabetes and Vitamin D

• Vitamin D metabolism and actions
• Epidemiology of hypovitaminosis D
• Association of low Vitamin D status and
chronic diseases
• Association of low vitamin D and diabetes:
– epidemiological evidence,
– pathophysiological plausibility,
– efficacy of interventions
The primary function of calcitriol
or 1,25 (OH)2D3 in the intestine
is increased absorption of
calcium and phosphorous.
Vitamin D is carried into the
nucleus of the enterocyte, where it
binds to receptor proteins and
acts as a steroid hormone,
resulting in the stimulation and
synthesis of new messenger RNA
molecules.
These messenger RNA molecules
are then translated to produce a
protein, Calbindin, a calcium
binding protein in the intestinal
mucosa that is synthesized in
response to the action of calcitriol
(active vit. D). This calcium
binding protein is needed for Ca
transport across the cell
membranes
Calcitriol and the Bone:
PTH, alone or with
calcitriol, directs the
mobilization of Ca and P
from the bones to help
achieve a normal blood Ca
concentration. The body’s
needs for calcium is
regulated by the
production of calcitriol by
the kidneys.
“Hypocalcemia” increases
the secretion of
parathyroid hormone,
which in turn:
a) Stimulates the
conversion of some of the
circulating 25(OH)2D3 to
1,25(OH)2D3 (calcitriol) in
the kidneys.
b) This active 1,25(OH)2D3
(calcitriol) then causes
elevation of serum Ca and
P by acting on kidney,
Vitamin D metabolism and actions

Maalouf NM, Current opinion in Nephrology and hypertension, 2008

 Calcium orotate ---
orotate as an electrolyte carrier, namely,
1) a low dissociation constant,
(2) an affinity for specific cellular systems or
organs, and
(3) a metabolic pathway which liberates the
transported mineral within the targeted organ or
system.
 Calcium orotate

Orotates are mineral salts of orotic acid . It is found in our body and also in dairy products.
It is believed that minerals and vitamins in orotate form act as superior transporters
throughout the body. When a mineral is in an orotate form, it can pass through cell
membranes easily without breaking apart so it can get to where it’s needed most - joints,
tissues, and cartilage. Orotate salts, being neutrally charged, pass easily through cell
membranes.In effect, orotate ferries the mineral atoms into cells and tissues, thus
producing higher concentrations.
calc
 Diabetes and Vitamin D
• Vitamin D metabolism and actions
• Epidemiology of hypovitaminosis D
• Association of low Vitamin D status and
chronic diseases
• Association of low vitamin D and diabetes:
– epidemiological evidence,
– pathophysiological plausibility,
– efficacy of interventions
Suggested terminology to describe vitamin D status
according to circulating 25(OH)D concentrations

25(OH)D
Stages of vitamin D concentrations
status (ng/mL)

Deficiency 0–12

Insufficiency >12–30
Adequacy >30 to 100
Toxicity >100

Souberbielle JC et al, Autoimmune reviews, 2010

 Causes of
Causes of hypovitaminosis
hypovitaminosis D
D
• Reduced skin synthesis
– Sunscreen use, skin pigment, aging, season, latitude
• Decreased bioavailability
– Malabsorption, obesity
• Increased catabolism
– Antconvulsants, glucocorticoids (binding to the steroid receptor)
• Breast feeding
– Poor vit D content in human milk
• Decreased synthesis of 25(OH)D
– Liver failure
• Increased urinary loss of 25(OH)D
– Nephrotic syndrome
• Decreased synthesis of 1,25(OH)D
– Chronic kidney failure
 Hypovitaminosis D: a global perspective

80% in aged,
42% in
adolescents
35-73%

89% in
adolescents

Midle East and Africa register the highest rates of hypovitaminosis D worldwide.
Turkish, Moroccan, Indian and Sub-Sahara African immigrants in Europe have
higher level of hypovitaminosis D compared to indigenous European populations
30-80%
50-97%

Bandeira et al, Arq Bras Endocrinol Metab 50, 2006 Mithal et al, Osteop Int, 2009

Van der Meer M et al, Ospeop Int, 2011

Serum 25(OH)D measured in elderly people in 16 European centers participating
in the Euronut SENECA Study.

The lowest values

were found in
Greece, Spain,
and Italy

Lips, P. Endocr Rev 2001;22:477-501

Copyright ©2001 The Endocrine Society

 Diabetes and Vitamin D
• Vitamin D metabolism and actions
• Epidemiology of hypovitaminosis D
• Association of low Vitamin D status and
chronic diseases
• Association of low vitamin D and diabetes:
– epidemiological evidence,
– pathophysiological plausibility,
– efficacy of interventions
 Vitamin D deficiency

􀂃 Rickets--------------Children
􀂃 Osteomalacia------ Adults
􀂃 Osteoporosis-------Adults

……….. And much more!!

Vitamin D deficiency
Independent Association of Low Serum 25-Hydroxyvitamin D Levels With All-
Cause and Cardiovascular Mortality
Dobnig H et al, Arch Intern Med. 2008;168(12):1340-1349.

Prospective cohort study

of 3258 patients undergoing
coronary angiography

Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349.

Copyright restrictions may apply.

 Cox proportional hazards regression model
ratios (including 95% confidence intervals
[CI]) for cardiovascular mortality are shown
for 25-hydroxyvitamin D (A) and 1,25-
dihydroxyvitamin D (B) quartiles (Q) for the
following 3 different statistical models (M):
(1) M1 (unadjusted), (2) M2 (adjusted for
age, sex, body mass index, and physical
activity level), and (3) M3 (variables of M2
plus active smokers, diabetes mellitus,
albumin level, cystatin C level, triglyceride
level, N-terminal pro-BNP level, systolic and
diastolic blood pressure, low-density
lipoprotein and high-density lipoprotein
cholesterol levels, and the use of statins,
aspirin, -blockers, bronchodilators, and
angiotensin-converting enzyme inhibitors)

Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently

associated with all-cause and CVD mortality
Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349.

Copyright restrictions may apply.

 Age-, Sex-, and Race-Adjusted Prevalence and ORs of Select Cardiovascular Disease Risk
Factors Between the First and Fourth Quartiles of Serum 25(OH)D Levels

Data From the Third National Health and Nutrition Examination Survey
(15088 participants >20 yrs)

Martins, D. et al. Arch Intern Med 2007;167:1159-1165.

Copyright restrictions may apply.

 Vit D and Metabolic Syndrome
Relation of 25-hydroxyvitamin D and PTH levels
with metabolic syndrome among US adults

JP Reis, D. von Muhlen, ER Miller

European Journal of Endocrinology, 159, 2008

We have strong evidences of hypovitaminosis D in MetS patients, independent of

Ca intake, PTH, BMI, or renal function

The potential mechanisms to explain the protective effect of vitamin D against MetS
is based on the effect on glucose homeostasis (insulin resistance, β cell function):
Vit D increases insulin receptor capacity and responsiveness for glucose transport
 Diabetes and Vitamin D
• Vitamin D metabolism and actions
• Epidemiology of hypovitaminosis D
• Association of low Vitamin D status and
chronic diseases
• Association of low vitamin D and diabetes:
– epidemiological evidence,
– pathophysiological plausibility,
– efficacy of interventions
 Association between type 1 diabetes mellitus and risk of hip fracture in case-control and
cohort studies.

Janghorbani M et al. Am. J. Epidemiol. 2007;166:495-505

American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins
Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
journals.permissions@oxfordjournals.org.
 Association between type 2 diabetes mellitus and risk of hip fracture in case-control and
cohort studies.

Janghorbani M et al. Am. J. Epidemiol. 2007;166:495-505

American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins
Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
journals.permissions@oxfordjournals.org.
BoneMineral
Bone Mineral Density
Density (BMD)
(BMD) at at the
the hip
hip in
in subjects
subjects with
with
diabetes type
diabetes type1,
1, diabetes
diabetes type
type 22 and
and without
without diabetes
diabetes

1 P<0.05
P<0.005
0,9
0,8
0,7

0,6
Type 1
0,5
Type 2
0,4 Controls

0,3
0,2
0,1
0
Men Women

Tuominen et al, Diabetes Care, 1999

 Bone quality
Bone quality vs
vs bone
bone density
density

Diabetes is associated
with a decrease in bone
strength that is not
reflected in the
measurement of BMD

Despite having a higher bone density, on average, patients with T2D have a
higher risk of fractures. Other factors, associated with frailty and falls,
including age, physical activity and BMI do not account for the association
between T2D and fracture.
Has Fat
Has Fat aa Protective
Protective Role
Role for
for the
the Skeleton?
Skeleton?
“Pros &
“Pros & Cons”
Cons”

Decreased Vit D bioavailability

Rosen CJ et al. Nature, 2006

Roleof
Role ofvitamin
vitaminDDin
inthe
thepathogenesis
pathogenesisof
oftype
type22Diabetes
DiabetesMellitus
Mellitus

Palomer et al, Diabetes, Obesity and Metabolism, 2008

 Serum Vitamin D and Subsequent
Occurrence of Type 2 Diabetes
Two nested case-control
studies, collected by the
Finnish Mobile Clinic in
1973–1980. During a follow-
up period of 22 years, 412
incident type 2 diabetes
cases occurred, and 986
controls were selected by
individual matching.

Study- and sex-specific and pooled age-adjusted relative odds of type 2 diabetes comparing highest and lowest
quartiles of serum vitamin D. The black squares and horizontal lines represent study- and sex-specific ORs and
95% CIs, respectively. The area of the black squares reflects the study- and sex-specific weight (inverse of the
standard error). The diamond represents the pooled ORs and 95% CI. The vertical dashed line represents the
pooled relative risk.

Knekt: Epidemiology, Volume 19(5).September 2008.666-671

Pittas AG et al, Diabetes Care, 33(9) 2010
Levelsof
Levels of vitamin
vitaminDDand
andcardiometabolic
cardiometabolicdisorders:
disorders:
Systematicreview
Systematic reviewand
andmeta-analysis
meta-analysis

Parker J et al, Maturitas, 2009

Factors Contributing to Low
Vitamin D Levels in Diabetes
Diabetes Care, 33(10), 2010
 Vitamin D and diabetes
The metabolically active form of vitamin D,
1,25(OH)2D3, and its analogues have been
shown to have effects on the major players
involved in the pathogenesis of type 1 and type
2 diabetes. Beta cell function has been shown
to be improved by 1,25(OH)2D3 in vitro and in
vivo, and the avoidance of vitamin D deficiency
is essential for normal beta cell function. In
NOD mice, 1,25(OH)2D3 protects against
insulitis, diabetes and disease recurrence after
islet transplantation, primarily through
immunomodulatory effects.

Review
Vitamin D and diabetes
C. Mathieu et al, Diabetologia, 2005
 Evidence of the efficacy of Vit D
supplementation
Vitamin D improves endothelial function in
patients with Type 2 diabetes mellitus and low
vitamin D levels
J. A. Sugden, J. I. Davies, M. D. Witham,et al
DIABETIC Medicine, 2007
Daily consumption of vitamin D-or vitamin D
+ calcium fortified yogurt drink improved
glycemic control in patients with type 2
diabetes: a randomized clinical trial
Nikooyeh B, Neyestani TR, Farvid M et al
AJCN, 2011
Vitamin D as an analgesic for patients with T2D
and neuropathic pain
Lee P, Chen R.
Arch Intern Med 2008
 Schematic representation of the multitude of other potential physiologic
action of vitamin D for cardiovascular health, cancer prevention,
regulation of immune function and decreased risk of autoimmune diseases

Holick, Am J Clin Nutr, 2004

November, 2010
 Major challenges
• Measuring 25(OH)D
– Techniques available

– Clinical reporting of circulating 25(OH)D

concentrations

• Defining doses of Vitamin D supplements

Recommendations for
Recommendations for clinical
clinical practice
practice

Souberbielle JC et al, Autoimmunity reviews, 2010

 Vitamin D3
Vitamin D3is
is more
morepotent
potent than
than Vitamin
VitaminD2
D2 in
in humans
humans

D2

D3

Heaney, R. P. et al.
J Clin Endocrinol Metab 2011;96:E447-E452

Copyright ©2011 The Endocrine Society

 Conclusions
• The role of Vitamin D in diabetes is not limited to
the autoimmune form of diabetes

• The relationship between vitamin D and diabetes

is complicated, involving various mechanisms
not yet fully elucidated

• Clinical trials are required to identify individuals

with or at risk of T2D that will most benefit from
Vitamin D supplementation and the dose and
formulation which would be most effective